Normal control of breathing is a complex process that involves, in part, the body's interpretation and response to chemical stimuli such as carbon dioxide, pH and oxygen levels in blood, tissues and the brain. Normal breathing control is also affected by other factors such as wakefulness (i.e., whether the patient is awake or sleeping), emotion, posture and vocalization. Within the brain medulla, there are respiratory control centers that interpret various feed-forward and feed-back signals that affect respiration by issuing commands to the muscles that perform the work of breathing. Key muscle groups are located in the abdomen, diaphragm, pharynx and thorax. Sensors located centrally and peripherally then provide input to the brain's central respiration control areas that enables response to changing metabolic requirements.
For example, ventilation sufficient to meet the body's metabolic needs is maintained primarily by the body's rapid response to changes in carbon dioxide (CO2) levels. Increased CO2 levels (hypercapnia) signal the body to increase breathing rate and depth, resulting in higher blood oxygen levels and subsequent lower blood CO2 levels. Conversely, low CO2 levels (hypocapnia) can result in periods of hypopnea (decreased breathing) or, in the extreme case, apnea (no breathing) since the stimulation to breathe is diminished.
There are many diseases in which loss of normal breathing control is a primary or secondary feature of the disease. Examples of diseases with a primary loss of breathing control are sleep apneas (central, mixed or obstructive; where the breathing repeatedly stops for 10 to 60 seconds) and congenital central hypoventilation syndrome. Secondary loss of breathing control may be due to chronic cardio-pulmonary diseases (e.g., heart failure, chronic bronchitis, emphysema, and impending respiratory failure), excessive weight (e.g., obesity-hypoventilation syndrome), certain drugs (e.g., anesthetics, sedatives, sleeping aids, anxiolytics, hypnotics, alcohol, and narcotic analgesics and/or factors that affect the neurological system (e.g., stroke, tumor, trauma, radiation damage, and ALS). In chronic obstructive pulmonary diseases where the body is exposed to chronically high levels of carbon dioxide, the body adapts to the respiratory acidosis (lower pH) by a kidney mediated retention of bicarbonate, which has the effect of partially neutralizing the CO2/pH respiratory stimulation. Thus, the patient is unable to mount a normal ventilatory response to changes in metabolic demand.
Sleep disordered breathing is an example of where abnormalities in the control of breathing lead to a serious and prevalent disease in humans. Sleep apnea is characterized by frequent periods of no or partial breathing. Key factors that contribute to these apneas include anatomical factors (e.g., obesity), decreased hypercapnic and hypoxic ventilatory responses (e.g., decreased response to high carbon dioxide and low oxygen levels, respectively) and loss of “wakefulness” (i.e., respiratory drive to both lungs and/or to pharyngeal dilator muscles during sleep). Apneic events result in hypoxia (and the associated oxidative stress) and eventually severe cardiovascular consequences (high blood pressure, stroke, heart attack).
Estimates for U.S. individuals afflicted with conditions wherein there is compromised respiratory control include sleep apneas (15-20 millions); obesity-hypoventilation syndrome (3-5 millions); chronic heart disease (5 millions); chronic obstructive pulmonary disease (COPD)/chronic bronchitis (10 millions); drug-induced hypoventilation (2-10 millions); and mechanical ventilation weaning (0.5 million).
Drugs are most often eliminated by biotransformation and/or excretion into urine, feces or bile. The liver is the major organ for xenobiotic biotransformation, and is thereby important in characterizing the metabolic stability, toxicology, and drug-drug interaction properties of drugs. Drug metabolism is achieved via two major liver-located enzyme reactions: Phase I and Phase II reactions. Phase I enzymes include the cytochrome P450 (CYP450) family of enzymes, which are located in the smooth endoplasmic reticulum. The basic processes in Phase I reactions are oxidation, reduction and/or hydrolysis, many of which are catalyzed by the CYP450 system and require NADPH as a cofactor. Phase II enzymes are located in the cytoplasm and endoplasmic reticulum, and perform conjugation reactions including glucuronic acid, glutathione, sulfate, and glutamine conjugations. Phase II reactions generally inactivate the drug if it is not already therapeutically inactive following Phase I metabolism, and also make the drug more water soluble to facilitate its elimination. Some drugs are metabolized by Phase I or Phase II enzymes alone, whereas others are metabolized by both Phase I and Phase II enzymes (Baranczewski et al., 2006, Pharmacol. Rep. 58:453-472). Microsomes are subcellular liver tissue fractions (membrane vesicles of the smooth endoplasmic reticulum) and contain the Phase I CYP450 family of enzymes. Compounds undergo only Phase I metabolism in liver microsomes in the presence of NADPH cofactors. Significant parent-drug disappearance in the presence of liver microsomes thus indicates that the drug will be significantly modified by the CYP450 enzymes in the body (Rodrigues, 1994, Biochem, Pharm. 48(12):2147).
The purpose of a pharmacokinetic (PK) study is to use drug concentration-time profiles and associated pharmacokinetic parameters to understand how the drug is processed, modified, distributed and/or eliminated upon administration to an animal. In drug discovery, a pharmacokinetic study is performed to (1) guide dosage regimen design for animal efficacy and toxicity studies, (2) understand and interpret pharmacology and toxicology study results, and (3) select the drug candidates with desired pharmacokinetic properties for the disease indication intended. The PK data from the animal studies can be extrapolated to predict PK profiles in humans so as to select and optimize dosage regimens for a drug candidate in human clinical trials.
There is a need in the art for novel compounds useful for restoring all or part of the body's normal breathing control system in response to changes in CO2 and/or oxygen levels, with minimal side effects. Further, there is a need in the art for novel compounds useful for restoring all or part of the body's normal breathing control system, that possess suitable metabolic stability and suitable pharmacokinetic properties, such as oral bioavailability. Further, there is a need in the art for novel compounds useful for restoring all or part of the body's normal breathing control system, that can be administered orally and used in a chronic manner, as well as acutely, via methods including intravenous administration. The present invention addresses and meets these needs.